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Safety and Efficacy Study of Neratinib and Cetuximab to Treat Patients With Quadruple Wild-Type Metastatic Colorectal Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01960023
Recruitment Status : Withdrawn (This registry was planned to report on the Phase II portion of the study. NSABP decided not to proceed with the Phase II portion of the study.)
First Posted : October 10, 2013
Last Update Posted : March 4, 2019
Information provided by (Responsible Party):
NSABP Foundation Inc

Brief Summary:

The FC-7 study is designed as an open label, single arm, Phase I/II dose-escalation study evaluating the combination of neratinib and cetuximab in patients with metastatic colorectal cancer primary tumor that is "quadruple wild-type " (wild-type KRAS, NRAS, BRAF, PIK3CA). The primary aim in the Phase I portion of this study is to determine the safety and tolerability of the two-drug combination. The primary aim of the Phase II part is to determine the overall objective response rate (complete and partial responses) by Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

Patients will receive concurrent therapy with cetuximab (400 mg/m2 IV loading dose followed by 250 mg/m2 IV weekly), and neratinib.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Drug: Cetuximab Drug: Neratinib Phase 1 Phase 2

Detailed Description:

The neratinib dose-escalation using a 3+3 design will include 4 dose levels (120 mg, 160 mg, 200 mg, and 240 mg) as a daily oral dose. Up to 12 patients will be treated at the maximum tolerated dose (MTD).

The neratinib dose-escalation for the study will proceed on the basis of dose-limiting toxicity (DLT) during cycle 1. DLT will be defined as the occurrence of 1 or more of the following events during cycle 1: any grade diarrhea that is associated with fever or dehydration requiring IV fluids; grade 3 diarrhea lasting more than 2 days on optimal medical therapy; grade 4 diarrhea of any duration; grade 3 or 4 neutropenia associated with fever; grade 4 neutropenia lasting more than 7 days; grade 4 thrombocytopenia; grade 3 or 4 non-hematological toxicity (excluding grade 3 rash or allergic reaction/hypersensitivity); or any toxicity-related delay of more than 2 weeks to initiate cycle 2. Patients will be enrolled at the next dose level when all evaluable patients at the same dose level have completed the first treatment cycle. Enrolled patients will remain on the assigned dose level treatment until toxicity or disease progression.

The Phase II part of this study will proceed with a two-stage design with a maximum of 46 patients. Between 6 and 12 patients at the Phase I MTD level will be included in the Phase II, stage-one analysis.

Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0.

Submission of tumor and blood samples for FC-7 correlative science studies will be a study requirement for all patients. A core biopsy procedure to procure fresh tumor samples from an accessible site of metastasis will be performed before study dose level assignment (after the patient has signed the consent form and has been screened for eligibility).

Optional biopsy samples of metastatic disease will be procured from consenting patients after Cycle 1 of treatment and at the time of disease progression.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Dose-Escalation Study Evaluating the Combination of Neratinib and Cetuximab in Patients With "Quadruple Wild-Type" (KRAS/NRAS/BRAF/PIK3CA Wild-Type) Metastatic Colorectal Cancer Resistant to Cetuximab
Study Start Date : October 2013
Actual Primary Completion Date : July 13, 2016
Actual Study Completion Date : July 13, 2016

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Arm 1: Cetuximab and Neratinib
Cetuximab 400 mg/m2 IV loading dose followed by weekly cetuximab 250 mg/m2 IV plus neratinib per oral daily until disease progression
Drug: Cetuximab
400 mg/m2 IV loading dose followed by weekly cetuximab 250 mg/m2 IV until disease progression

Drug: Neratinib

Phase I portion of the study:

Dose level 1: 120 mg/day; Dose level 2: 160 mg/day; Dose level 3: 200 mg/day; Dose level 4: 240 mg/day

Phase II portion of the study: The recommended dose determined in the Phase I portion of the study.

Primary Outcome Measures :
  1. The safety and tolerability of cetuximab and neratinib during the Phase I portion of the study. [ Time Frame: From start of study therapy weekly through disease progression or end of therapy, approximately 2 years ]
    Number of patients experiencing dose limiting toxicities (DLT).

  2. Number of patients with Overall response rate (ORR)(complete response/partial response) and progression free survival (PFS) during the Phase II portion of the study [ Time Frame: From start of study through 16 weeks. ]
    Response as measured by RECIST 1.1 criteria.

Secondary Outcome Measures :
  1. Progression-free survival (PFS). The time to progression and the time to progression based on tumor HER2 status. [ Time Frame: From start of study through disease progression or end of therapy, approximately 2 years ]
  2. Tumor measurement to determine objective tumor decrease and stable disease [ Time Frame: From start of study through desease progression or end of therapy, approximately 2 years ]
    Measurement of disease status by continuous tumor measurement.

  3. Measure molecular and genetic correlatives for neratinib and cetuximab [ Time Frame: Baseline (prior to treatment assignment), prior to therapy, after completion of cycle 1, and at disease progression approximately 2 years. ]
  4. The frequency and severity of adverse events to evaluate the overall toxicity in the Phase II portion of the study. [ Time Frame: From start of study therapy through 30 days after end of therapy, approximately 2 years ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion criteria:

  • Patients with resected primary must be active participants of the NSABP Patient Registry and Biospecimen Profiling Repository (MPR-1) study. Patients with intact primary and metastatic KRAS wild-type disease at presentation (treatment naive), must have signed consent for quadruple wild-type central testing for treatment-naive tumor sample submission
  • The Eastern Cooperative Oncology Group (ECOG) performance status must be 0, 1, or 2.
  • Patients must have the ability to swallow oral medication.
  • The tumor tissue must have been determined to be KRAS, NRAS, BRAF, PIK3CA wild-type by central CLIA testing.
  • There must be documentation by PET/CT scan, CT scan, or MRI, that the patient has evidence of measurable metastatic disease per RECIST criteria.
  • Patients must have an accessible metastatic lesion for pretreatment core biopsy procurement.
  • Unless either drug is medically contraindicated, patients must have received oxaliplatin and irinotecan as part of standard chemotherapy regimens. (This includes adjuvant therapy.)
  • Patients must have had at least one prior treatment for metastatic disease with standard chemotherapy and cetuximab in combination or as monotherapy. [Note: patients who received panitumumab instead of cetuximab are eligible.]
  • At the time of study entry, blood counts performed within 4 weeks prior to study entry must meet the following criteria: absolute neutrophil count (ANC) must be greater than or equal to 1000/mm3; Platelet count must be greater than or equal to 100,000/mm3; Hemoglobin must be greater than or equal to 9 g/dL
  • The following criteria for evidence of adequate hepatic function performed within 4 weeks prior to study entry must be met: Total bilirubin must be less than or equal to 1.5 x upper limit of normal (ULN); aspartate aminotransferase (AST) and ALT must be less than or equal to 2.5 x ULN for the lab or less than or equal to 5 x ULN if liver metastasis;
  • Serum creatinine performed within 4 weeks prior to study entry must be less than or equal to 1.5 x ULN for the lab.
  • Female patients and male patients with female partners of reproductive potential must agree to use an effective method of contraception during therapy and for at least 6 months after the last dose of study therapy.
  • Patients with acquired immunodeficiency syndrome (AIDS-related illnesses) or known human immunodeficiency virus (HIV) disease must: Have a CD4 count greater than or equal to 200 cells/uL within 30 days prior to beginning study therapy; Be off all antiretroviral therapy (prophylaxis/treatment) greater than 60 days prior to beginning study therapy; Have no evidence of opportunistic infections.

Exclusion criteria:

  • Diagnosis of anal or small bowel carcinoma.
  • Colorectal cancer other than adenocarcinoma, e.g., sarcoma, lymphoma, carcinoid.
  • Previous therapy with any HER2 TKI (such as trastuzumab, lapatinib, neratinib, etc.) for any malignancy.
  • Symptomatic brain metastases or brain metastases requiring chronic steroids to control symptoms.
  • Active hepatitis B or hepatitis C with abnormal liver function tests.
  • Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease or condition significantly affecting gastrointestinal function.
  • Persistent Common Toxicity Criteria for Adverse Effects (CTCAE v4.0) greater than or equal to grade 2 diarrhea regardless of etiology.
  • Chronic daily treatment with corticosteroids with a dose of greater than or equal to 10 mg/day methylprednisolone equivalent (excluding inhaled steroids).
  • CTCAE v4.0 grade 3 or 4 anorexia or nausea related to metastatic disease.
  • CTCAE v4.0 greater than or equal to grade 2 vomiting related to metastatic disease.
  • Any of the following cardiac conditions: Documented congestive heart failure; Myocardial infarction within 6 months prior to study entry; Unstable angina within 6 months prior to study entry; Symptomatic arrhythmia
  • Serious or non-healing wound, skin ulcer, or bone fracture.
  • History of bleeding diathesis or coagulopathy. (Patients on stable anticoagulant therapy are eligible.)
  • Symptomatic interstitial lung disease or definitive evidence of interstitial lung disease described on CT scan, MRI, or chest x-ray in asymptomatic patients; dyspnea at rest requiring current continuous oxygen therapy.
  • Other malignancies unless the patient is considered to be disease-free and has completed therapy for the malignancy greater than or equal to 12 months prior to study entry. Patients with the following cancers are eligible if diagnosed and treated within the past 12 months: carcinoma in situ of the cervix, colorectal carcinoma in situ, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.
  • Previous serious hypersensitivity reaction to monoclonal antibodies. (Determination of "serious" hypersensitivity reaction is at the investigator's discretion.)
  • Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements.
  • Pregnancy or lactation at the time of study entry.
  • Use of any investigational agent within 4 weeks prior to study entry.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01960023

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United States, Florida
University of Florida
Gainesville, Florida, United States, 32610
MD Anderson Cancer Center Orlando
Orlando, Florida, United States, 32806
United States, Idaho
Saint Luke's Mountain States Tumor Institute
Boise, Idaho, United States, 83712
United States, Illinois
Decatur Memorial Hospital
Decatur, Illinois, United States, 62526
United States, Michigan
Saint Joseph Mercy Hospital
Ann Arbor, Michigan, United States, 48106
Henry Ford Health System
Detroit, Michigan, United States, 48202
United States, North Carolina
Levine Cancer Institute
Charlotte, North Carolina, United States, 28204
Novant Health Presbyterian Medical Center
Charlotte, North Carolina, United States, 28204
United States, Pennsylvania
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, United States, 19107
Allegheny General Hospital
Pittsburgh, Pennsylvania, United States, 15215
University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15232
Reading Hospital and Medical Center
West Reading, Pennsylvania, United States, 19611
Sponsors and Collaborators
NSABP Foundation Inc
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Principal Investigator: Norman Wolmark, MD NSABP Foundation Inc

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Responsible Party: NSABP Foundation Inc Identifier: NCT01960023     History of Changes
Other Study ID Numbers: NSABP FC-7
First Posted: October 10, 2013    Key Record Dates
Last Update Posted: March 4, 2019
Last Verified: February 2019

Keywords provided by NSABP Foundation Inc:
Colorectal cancer

Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents